title: TXNIP deficiency exacerbates endotoxic shock via the induction of excessive nitric oxide synthesis.
abstract: Thioredoxin-interacting protein (TXNIP) has multiple functions, including tumor suppression and involvement in cell proliferation and apoptosis. However, its role in the inflammatory process remains unclear. In this report, we demonstrate that Txnip⁻/⁻ mice are significantly more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock. In response to LPS, Txnip⁻/⁻ macrophages produced significantly higher levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS), and an iNOS inhibitor rescued Txnip⁻/⁻ mice from endotoxic shock-induced death, demonstrating that NO is a major factor in TXNIP-mediated endotoxic shock. This susceptibility phenotype of Txnip⁻/⁻ mice occurred despite reduced IL-1β secretion due to increased S-nitrosylation of NLRP3 compared to wild-type controls. Taken together, these data demonstrate that TXNIP is a novel molecule that links NO synthesis and NLRP3 inflammasome activation during endotoxic shock.
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea ; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Suh
authors.forename: Dong Oh
authors.initials: DO
authors.lastname: Kim
authors.forename: Jeong-Ran
authors.initials: JR
authors.lastname: Park
authors.forename: Haiyoung
authors.initials: H
authors.lastname: Jung
authors.forename: Tae-Don
authors.initials: TD
authors.lastname: Kim
authors.forename: Suk Ran
authors.initials: SR
authors.lastname: Yoon
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Na
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Hee-Bong
authors.initials: HB
authors.lastname: Lee
authors.forename: Inpyo
authors.initials: I
authors.lastname: Choi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C445672:Txnip protein, mouse; D009569:Nitric Oxide; D013879:Thioredoxins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse